This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The significant amount of data generated by SIV vaccine studies has led to the suggestion that an HIV vaccine is achievable. The capacity of humoral and cellular immune responses in mucosal tissues to block or contain replication at the initial stage of virus transmission may have a profound impact on the ability of a vaccinated host to resist infection. The development of an effective vaccine that restricts viral replication at the mucosal portal of entry may be our best hope for controlling HIV infection. We believe there are two necessary features for a successful vaccine: 1) life-long stimulation of the immune system with viral antigens;and 2) a targeted immune response at the site of primary replication of HIV. A vaccine approach that simultaneously addresses these two issues would have the potential to achieve solid, long-term protection. To fulfill these requirements, we propose an alternative approach to successfully deliver a vaccine to mucosal sites and elicit protective mucosal immune responses. We propose to use the epithelial stem cell as a permanent source of viral antigen and their differentiated offspring as antigen producing presenting cells. Therefore, the goal is: 1) To investigate the best promoter that will be expressed exclusively in terminally differentiated epithelial cells;and, 2) To elicit SIV antigen expression from a terminally differentiated keratinocyte-specific promoter in rhesus macaques vaccinated by dermal, vaginal and rectal routes.